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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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« Business Books: The Enantiomers | Main | Hexacyclinol - Another Request »

February 19, 2009

Hexacyclinol: A Forensic Case

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Posted by Derek

Remember hexacyclinol? Some readers are probably groaning and thinking “Oh, yes, indeed”, which may make up for the ones who are saying “Remember what?”

Hexacyclinol is a complex natural product, but after that statement the arguing begins. James La Clair published a synthesis of it in 2006 in Angewandte Chemie, one of the most prestigious chemistry journals, but the reception of the paper did nothing to help the prestige of either La Clair or the journal. Readers immediately seized on odd spectral data and experimental details to ask whether the molecule had been made at all and just how well the manuscript had been refereed.

The story got even messier later in the year when synthetic organic chemist Scott Rychnovsky weighed in with a paper suggesting that the structure of the natural product had been misassigned to start with. This was followed by a synthesis by John Porco and his group of his proposed structure, which turned out to match the NMR spectra of the original natural product. Since they also had an X-ray crystal structure, you would think that this would have ended the argument, at least at the level of what hexacyclinol looks like. The argument about what La Clair actually made, though, continued. And La Clair himself suggested that he and Rychnovsky had made two different molecules that just happened to have very similar NMR spectra.

Now a paper in Organic Letters is trying to clear that part of the story up, saying that ” indeed, the possibility that two molecules as complex as 1 and 2 may have indistinguishable NMR spectra carries an uneasy feel.” The authors, Giacomo Saielli and Allesandro Bagno from the University of Padova, return to the two proposed structures and calculate both their carbon and proton NMR spectra using what appear to be the best methods available for estimating their shifts and coupling constants.

The second structure fits much, much better, and the authors conclude that there is “hardly any doubt” that it’s the correct structure for hexacyclinol. In fact, they go further:

”The structure of hexacyclinol is confirmed to be 2. Furthermore, if 1 had been synthesized or was formed from an unforeseen reaction, its NMR spectra are sufficiently different from those of 2 as to guarantee their distinction.”

Note the “if it had been synthesized”. As far as I can tell, the remaining questions in this case aren't chemical. They're psychological. The original Ang. Chem. synthesis is certainly incapable of generating the real structure of hexacyclinol, but it also appears incapable of making the structure it claims to have made. Taken together with its original odd features, you have to wonder just what it was: a hoax? An odd and pointless work of fiction? Self-deception? We’ll probably never know. All we know is what it isn't.

For more reactions oto this latest news, see The Curious Wavefunction and The Chemistry Blog.

Comments (43) + TrackBacks (0) | Category: Chemical News | The Scientific Literature


1. RB Woodweird on February 19, 2009 8:37 AM writes...

Ah, this brings back memories of the classic dustup between Cornforth and Chatterjee.

There is only one thing for it. La Clair must demand satisfaction. Saielli or Bagno (depends on who is senior) must answer with their choice of weapons. We will let this matter be settled where honor commands, on the moor at dawn.

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2. gyg3s on February 19, 2009 9:59 AM writes...

"Readers immediately seized on odd spectral data and experimental details to ask whether the molecule had been made at all ..."

Sigh. If only it had been patented rather than published in a journal.

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3. MTK on February 19, 2009 10:00 AM writes...

� indeed, the possibility that two molecules as complex as 1 and 2 may have indistinguishable NMR spectra carries an uneasy feel.�

While obviously not the case in this instance, the possibility of diastereomers of a natural product with distal stereocenters having indistinguishable spectral and physical properties has been neatly demonstrated by Curran et al.

In the above paper they were able to synthesize all 16 diastereoisomers of murisolin and compare the spectra. All 16 stereoisomers were described by only six sets of NMR spectra.

The implication here is that for molecules with distal stereocenters comparison with spectra from other syntheses or from the naturally derived compound may mean squat without synthesis and disproof of alternate structures that could have identical spectra.

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4. Hap on February 19, 2009 11:13 AM writes...

The problem wasn't the odd experimental details [well, other than the (alleged) spectrum of hexacyclinol with the solvent peak (but no other peak) shifted (and a cryptic note explaining why?)], but the total lack of experimental details - while the schemes provided detail, there were no actual experimental procedures (or data) for anything other than the NMR spectra of the penultimate intermediate and hexacyclinol. That made people annoyed enough to ask other questions, and point out other aspects of the synthesis which made little sense without explanation (and other peculiarities, like the lack of on-site NMR and the street lab of the Bionic Brothers).

I think at this point Dr. La Clair is running out of goalposts to shift. And if a duel is joined, it's hard to tell who should participate - Rychnovsky, Porco, Saielli, Bagno, or any (or all) of their graduate students? It'd be more like the end of The Evil That Men Do, with sixty people with pickaxes chopping away at La Clair's car.

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5. acetylcholine on February 19, 2009 12:30 PM writes...

I've seen La Clair's lab notebooks. They're atrocious. There is no way that he could perform a synthesis beyond 10 steps by the way that he maintains his data, let alone serve as a guide to the unskilled Bionic Brothers he picked up off the street.

Shall we say it?
His Angew. paper was fabricated.
What shall we do about it?
Obviously, he'll never win a grant for a total synthesis project. Beyond that, any future funding proposals he might make would be under some serious scrutiny. Though given his current laboratory situation, I don't think he cares.

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6. Jose on February 19, 2009 12:45 PM writes...

I find it staggering in the AngewChem has not issued a full explaination, and no punishment. Sloppy data is one thing, but a fully fabricated synthesis is another kettle of fish altogether.

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7. Aspirin on February 19, 2009 1:18 PM writes...

I agree with #6. I find it astonishing that after all the hullabaloo and news and blog coverage, Angew Chem has still not published some kind of explanation or note.

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8. Hap on February 19, 2009 1:20 PM writes...

If its possible that NMR can't distinguish between the structure you've prepared and the actual structure of the natural product, then you need to provide more evidence than simply NMR data that you have made the correct product. La Clair's synthesis/fantasy didn't have any data other than NMR (and yields), and nothing to indicate what the structure of the product that his people made is, let alone its identity with the natural product. Making the wrong product is a honorable mistake, particularly when it's a complicated and involves novel reactions as this one did. People can even (as diazonamide A) make the wrong product with crystal structure support. As Dr. Lowe said above, there isn't even enough data to suggest that JJLC made what he claimed, much less actual hexacyclinol. The fact that no data for the synthetic intermediates has been provided over two years after the paper in response to repeated questions (but only lots of evasions) provides strong support that no synthesis of hexacyclinol was done by the LC crew.

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9. SRC on February 19, 2009 1:42 PM writes...

Little appreciated fact: two molecules of the same compound will generally have different NMR spectra, depending on the nuclear spin states in each. The NMR spectrum of a molecule would consist of a singlet for each set of chemically equivalent protons.

What we normally see as the NMR spectrum is an average over the ensemble.

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10. anon on February 19, 2009 1:47 PM writes...

A link to chembiochem with a La Clair paper:

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11. MTK on February 19, 2009 2:38 PM writes...

Leaving the LeClair part of this story aside for now.

The title of the current Org. Lett paper asks "Can two molecules have the same NMR spectrum?" As shown in the Curran paper I cited above, the answer is "Absolutely."

So Hap is right. Even if the 1H and 13C NMR of what you've prepared is indistinguishable from that of the natural product that does not necessarily mean that you have made the actual natural product. You either need additional evidence on what you made or you need to make all the other reasonable alternatives to rule out identical NMR's.

I would be very interested to see what the DFT predictions of NMR spectra for those compounds that Curran made and found identical spectra for would be.

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12. James La Clair on February 19, 2009 3:32 PM writes...

I am glad that discussions are continuing...

Its sad to see that you all have to still take pot shots at me personally while I gather few of you have ever seen me work or worked with me.

For the record:

"I've seen La Clair's lab notebooks. They're atrocious." My notebooks are digital and are quite organized. Sorry not true.

"Obviously, he'll never win a grant for a total synthesis project."
It would be a sad world if chemists blackballed each other destroying each others careers for sport.

Jim La Clair

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13. Derek Lowe on February 19, 2009 3:52 PM writes...

Glad to see you here, although I confess that I'm surprised. My intention isn't so much to take pot shots at you as to figure out what exactly happened here. You have to admit, from outside it's a mystery.

I've certainly never seen your notebooks; there's no way for me to verify who that commenter is who claims to have. And I certainly have no wish to destroy anyone's career.

But the mystery remains. . .

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14. milkshake on February 19, 2009 4:06 PM writes...

like with the Blagojevich affair, the guts and lunacy of the main character are admirable

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15. Sili on February 19, 2009 4:47 PM writes...

I remember this (now that you mention it) from the old Tenderbutton.

Musta been one of the first posts I read.

(If you wanna see "atrocious" I should dig up my labbooks ...)

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16. weirdo on February 19, 2009 4:57 PM writes...

One of the beauties of science is that, often but not always, there are legitimate solutions to disagreements. We sometimes call this data.

Numerous well-respected chemists have published papers that contain data that refute the conclusions of the original paper. La Clair has published no data to refute the refutations.

Completely unbiased third-parties have but one conclusion to draw from this.

Derek was far too nice to Sir La Clair.

(No disrespect intended.)

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17. Acetylcholine on February 19, 2009 5:16 PM writes...

This is not a pot shot, as it is neither random nor lacking in careful thought, though in retrospect, with your inability to provide the scientific community with the desired synthetic evidence of your hexacyclinol, can you expect anything less?

Your own words:
J La Clair
June 6th, 2006 | 6:44 am
"Thanks for all the comments. It is good to pick on science and those who do. It should be done more often and to all faculty just not the ones who will not influence your careers. I will be at the San Fransisco ACS meeting (Total Synthesis section) and the Natural Products Gordon Conference if anyone would like to meet me in person."

I mean come on, its been two years since that packed room at ACS San Francisco (the topic was total synthesis, but you avoided so much in the way of synthesis and slathered in so much biology to purposefully confuse the audience, esp. that bit of speaking without a mic and walking back and forth in front of everybody and not up at the podium) and we've heard nary an explanation. Not even a peep.

So no, it is not blackballing given such an abundance of, or in this case, lack therof, data, after all this time. And beyond data, your stories of Bionic Bros. unskilled 'technicians' picked up off the street, and 30+step kilo-scale synthetic enterprises in facilities that lack NMR...all on your own dime? And $15k for your starting material......hmmmm.

To quote the great Derek Lowe:
July 24th, 2006 | 7:45 am
"Jose, the best example I can think of is a Tet. Lett paper on alkaloid synthesis by one Samir Chatterjee (1979, p. 3249). John Cornforth turned right around and demolished it in a later issue (1980, p. 709). Here’s his abstract:

A polemic. All claims in the paper cited (Tetrahedron Letters 1979, 3249), which describes the prepn. of an intermediate for aconitine prepn., should be accepted as fact after, but not before, verification by independent expt.

To the best of my knowledge, nothing was ever heard from Chatterjee again."

Last I heard from JJLC?"
July 29th, 2006 | 11:34 am
"I am repeating this entire project to satisfy all of your concerns. I will be publishing further data sets on this work and if desired please email me (see manuscripts for current email address) and I can send preprints to you individually so you can critically analyze them before they hit the journals."

Two years later......nothing.

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18. James La Clair on February 19, 2009 5:46 PM writes...

Nothing has changed here. I have been working on this since the ACS and before not as fast I gather you would like me to.

I agree lets talk about science but lets leave my "notebooks" and "personal ticks" out of it.

I got close to a second generation approach that failed due to a badly planned RCM on my part (was rather unpublishable). I retooled and trickling forward. I put my progress up at the last 2008 Natural Products GRC and yes I am not speaking often as I am at the bench most days of the week. and the others like today writing.


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19. RTW on February 19, 2009 5:55 PM writes...

It's likely that several other names in natural product synthesis will weigh in on the controversy. I suspect a couple other labs are actively pursuing alternative routes and other means of reproducing the natural products. Some of the better natural product researchers like Wender, Trost, Keck, Roush, and Nicolaou might already have had their interest peaked by this issue, and might have put a grad student or two on the problem. Some of these guys are very competitive... I doubt we have heard the last on this one.

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20. InfMP on February 19, 2009 10:51 PM writes...

Don't do a second generation approach. Just publish the spectra of ALL of those new compounds like the rest of the competent chemistry world does (or the FIDs ;-)

No longer have them?
Re-synthesizing may be arduous, but it will clear your name.

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21. Alkaloid on February 19, 2009 11:40 PM writes...

Barry Bonds, Roger Clemons...James La Clair?

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22. Alkaloid on February 19, 2009 11:42 PM writes...

Oops...Clemens. Eh, not a baseball fan anyway.

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23. Anonymous on February 20, 2009 12:38 AM writes...

Where is this JL Liar guy and what is he doing? Hopefully he doesnot do anything that hurts people's health directly.

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24. Matt on February 20, 2009 12:39 AM writes...

Where is this JL Liar guy and what is he doing? Hopefully he doesnot do anything that hurts people's health directly/indirectly.

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25. Hap on February 20, 2009 12:48 AM writes...

Dr. La Clair,

Most times when one publishes communications, one also publishes at least spectra of the intermediates if not full experimentals as SI. That provides evidence that the synthesis was performed, and the experimentals allow someone (if they wish, which isn't often) to reproduce the work. Your synthesis paper had three NMR spectra as SI, one of which had a solvent peak shifted in a way no one seems to be able to explain. Thus, when Profs. Rychnovsky, Porco, Saielli, and Bagno publish their findings (concluding that the putative structure of hexacyclinol can't be hexacyclinol, and that the NMR spectra of the structures are distinguishable by inspection), there isn't anything left to make people believe that the synthesis was done. If the yields don't characterize the compounds (they're just numbers, not particular to any one compound), and if the NMR spectra don't either (for those compounds which have them), then there isn't any data in the paper which supports the contention that the compounds were prepared.

The logical course of action, as has been noted, would be to publish the experimental details and spectra of the intermediates in your synthesis, which should be around anyway (because you had to have characterized the compounds anyway to know what you had and to figure out whether your reactions worked anyway). That way, people would know that your synthesis had been done (which would still be a pretty good achievement, considering the complexity of the target) and, if there are unrealized complications with the NMR spectra of hexacyclinol and its putative structure, they could be resolved. Angewandte would probably be happier, because their judgment in accepting the article would be validated (and their reputation would be significantly improved), and people would stop complaining about your synthesis and questioning its validity. Instead of doing that, you've complained about people impugning your character and that of your synthesis for roughly the last two years, which seems not helpful (and counterproductive, if you would like the criticism to cease). If releasing the data is a simple and satisfactory solution to the problem, then not releasing it (after more than two years) seems like a peculiar thing to do. People don't really need or want another new synthesis of the putative structure of hexacyclinol - they just want to know whether the one published is accurate or not, and complaining about your treatment doesn't help to achieve that. Only showing your data does.

I don't think anyone here has a particular dislike for you personally. Most of us (or at least me, anyway) haven't met the people most known in chemistry - we know them by their work, and mostly by their papers. If their papers are logical, well-written, and cohere logically, or if they do neat things, or allow people to do things they hadn't been able to do before, then people are likely to respect more the people who did the work. If papers are sloppy, don't fit logically, or have logic not well-supported by their data, then people are likely to have less respect for the people who wrote them. That is probably one of the better aspects of science, that we can be judged on what we have done rather than other less relevant characteristics. When people are gone, our work and word will be much of what is left, and if either are bad, we will not be viewed kindly by those after us (if at all).

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26. Hap on February 20, 2009 1:05 AM writes...

The problem with using murisolin as a test case for spectral simulation is that the same functionality is present in its stereoisomers, murisolin has a modular structure (the bi-THF stereo is separated from the dihydrofuranone stereo), and while the stereo probably affects the conformation of the various diastereomers, there are lots of single bonds to rotate around to mitigate problems. The structures of hexacyclinol are different in functionality (though similar) and have lots of rings stuck together so that changes in stereo should lead to spectral changes because of the constrained rings. Murisolin is a significantly harder test for spectral simulation than hexacyclinol, and so failing the murisolin test wouldn't necessarily mean that the results for hexacyclinol are inaccurate. Failing the hard test doesn't mean that the method will fail an easier one.

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27. Jack Bauer on February 20, 2009 3:41 AM writes...

Personal attacks certainly aren't called for. The bigger issue here is the lack of referring. In a perfect world every publication should have full experimental data, exact procedures, and more then just a hydrogen and carbon spectra. We chemists are too trusting. If another group can't reproduce the synthesis (if they ever felt so inclined) then it shouldn't even be worth publishing.

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28. Ubin on February 20, 2009 4:29 AM writes...

Hello Dr. La Clair,

Just to echo commenter #20, why not simply repeat the synthesis already published instead of coming up with a second generation approach? Reproducing your work -if possible (which people doubt)- will lay most criticisms to rest.

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29. Just wondering... on February 20, 2009 5:02 AM writes...

Just two quotes from the JJLC Angewandte paper.

“Confirmation of this yield was established by the most-recent campaign that provided 3.6 g of 3a [...] Exposure of 3a to singlet oxygen resulted in a [2+2+2] cycloaddition [in 82% yield] that afforded a mixture of chromatographically separable 1 [Hexacyclinol] and 2 (8:1) [...]”

“The optical rotation of synthetic 1 [… ] +131.58) was comparable to that obtained in samples of isolated 1 [...] +132.28 as well as that reported by Graefe and co-workers [...]+130.58 thereby confirming the absolute stereochemistry of hexacyclinol.”

My conclusions: a) there is really a need for a second generation approach: 3.6 g, come on that is nothing; b) by coincidence, not only the NMR data but also the optical rotation is identical.

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30. RB Woodweird on February 20, 2009 7:26 AM writes...

I believe that the consensus of the group is that shenanigans has been properly called and a double dog dare is now in effect. Dr. La Clair must respond directly with experimental details and spectral data from the original synthesis or copies of his electronic notebook or he will be given such a wedgie that the Nobel committee may establish a new award to honor it.

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31. sepisp on February 20, 2009 8:12 AM writes...

What I find interesting is that La Clair's proposed structure contains a peroxide bond, which should be easy to prove by other methods than plain 1H/13C NMR.

Also, I wouldn't feel comfortable releasing the result but not doing NOESY on such a complex molecule.

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32. MTK on February 20, 2009 8:30 AM writes...


I certainly realize everything that you have said about murisolin.

I'm not trying to disprove the methods used by Saielli and Bagno. In fact, quite the opposite. DFT calculations that would generate substantially identical spectra for different compounds with known identical spectra, would bolster their case substantially.

So I brought it up due to two things:

a) As a general answer to the titular question of from Saielli and Bagno, "Can two molecules have the same NMR spectrum?"

b) As an inverse test to what they did in their paper. Of course, it's a harder test. That's what we do as scientists.

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33. Pd on charcoal on February 20, 2009 9:37 AM writes...

Hi Dr. La Clair. Personal remarks are certainly uncalled for. But right now I think you have to admit that the evidence for the other structure of hexacyclinol has built up to the point where the burden of proof is on you. As scientists, that's all we are asking for and I suspect you would have taken the same position. I think most of us would not only be satisfied but happy if you can refute the new results with one or two decisive pieces of data. For starters, how about the C13 NMR of your original compound which still does not seem to be around?

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34. HOMO-LUMO on February 20, 2009 9:56 AM writes...

First time, I heard from the La Clair case it was at old Tenderbuttom. I was with a colleague at that time with 10+ years of synthetic experience.

Rather than paying attention to all the fuzz created at that time in the blog, this guy was looking to all the spectra. He was clearly impressed with the fact that any of the displayed spectra had residual solvent peaks, no noise, and even more, no presence of a single chloroform satellite peak. His exact words were "Nice NMR predicting software..."

Personally, I am very happy that Dr. LaClair, published that article, it clearly highlights how imperfect and arbitrary still is the scientific refereeing system. I am sure that sometimes in big labs may arise cases of misleading scientific conduct which otherwise would not be tolerated from small groups/groups from light-weight countries in terms of science.

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35. Big Biotech on February 20, 2009 2:00 PM writes...

The isn't so much with Leclair, but with ACI for publishing sub-par work. I don't know this guy, but I assume he did a PhD/PDF with a big name and, thus, has many many useful contacts. Reality is, most of the referees for his paper were buddies who just let in sub-par work. Granted, a good scientist would not submit sub-par work, but a good referee would not recommend its publication.

If the peer review process were blinded, i.e. by removing authors names, it would be fairer. This is clearly imperfect, as it will still be possible, to a limited degree, to tell who wrote what, but it would level the playing field.

Is there any reason not to remove authors names, aside form giving the big boys (who run the journals) a better shot at publication?

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36. Jose on February 20, 2009 4:12 PM writes...

Anyone want to hazard a guess as to the chances of two different highly complex architectures having the same optical rotations within 1%? That 1% alone should give pause; I've taken a lot of alphas, and that is pretty damn tough, esp when compared to natural isolates, which always seem to have enough gremlins to skew things slightly.

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37. Bill on February 21, 2009 12:18 PM writes...

I got involved in the earlier discussions and was suspicious from the start. However what finally convinced me was comparing the original proton spectrum from Austria, Porco's spectrum and the
LeClair specrum plus the tabulated spectral data in the original Austrian paper (which failed to list some small but well-resolved long range couplings and which accidentally exchanged two
proton assignments which were correctly given in a patent application). Porco's spectrum was identical to the original spectrum. However,
LeClair's spectrum exactly reproduced the data from the original table, including all errors and
omissions from that table, i.e the unlisted long range couplings and the pair of interchanged assignments. This, along with the absense of 13C satellites, the total absence of impurity peaks at
the end of a 37-step synthesis,etc. was enough to completely convince me.
With respect to the role of referees, one thing to always bear in mind is that it is now far easier to synthesize a spectrum than a complex organic compound and, if a spectrum looks too good to be true, be suispicious and demand further information. However, we also need to consider the role of the journal editor. We do not
know whether the referees were sloppy or, alternatively,they raised serious concerns that were overruled by the editor. He has the ultimate authority to accept or reject and should have been concerned about the lack of supporting data. Some explanation from the editor is long overdue.

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38. Smeels like Quinine on February 21, 2009 9:28 PM writes...

This whole thing rather strikes me as the quinine/aluminum powder conundrum. And the most likely resolution to the clohexanol issue will be along similar lines - 3rd party verification. Unfortunately theres 37 steps to repeat, not just the one in question. Maybe someone will work it onto a thesis at some point down the line and let it rest once and for all.

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39. Mad Chemist Chick on February 21, 2009 9:56 PM writes...

Bill from comment #37:

Do you have the reference for the Austrian paper available?

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40. HOMO-LUMO on February 22, 2009 8:07 AM writes...

Big biotech, totally agree with you, blind refereeing would the ideal system. Unfortunately, that would close the gap between big and small players, and at one point the gaps in funding would not be further justified.

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41. Bill on February 22, 2009 12:46 PM writes...

To Mad Chemist Chick: the original paper was B.Schlegel et al, Journal of Antibiotics, Vol. 55, 814 (2002).

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42. ChemSpiderMan on March 2, 2009 3:29 PM writes...

I co-authored another related article is: "Applying Computer-Assisted Structure Elucidation Algorithms for the Purpose of Structure Validation: Revisiting the NMR Assignments of Hexacyclinol" avialable here:

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43. GCOAT on November 15, 2012 9:45 PM writes...

Doc. La Clair! I've began my tot. syn. career when I first read your paper (for me 4 years ago. Now I am writing my PhD dissertation and I am still following your story :) Firstly, I wanted to thank you for the interesting conversations your work has generated - I agree with the other commenters- I think it was important that this work was published the way it was if nothing else but for this discussion. And I agree with your conclusions Dr. La Clair- to quote you from your site "...The author hopes that this incident inspires publishers, editors, reviewers and authors to advance more effective measures to check and require spectral data sets as a part of the publication process. In particular, there is currently a lack of tools for presenting raw data files along with publications."

In saying that; I wanted to put to you this question- could you please publish these raw data in some form? If not via a refereed Journal, than atleast could you please upload on to a random web server and give people the link so we can see that this work was done and your intermediates synthesized? Looking from here, you can make all of us eat our words very fast by doing exactly what you are advocating. Nothing is stopping you from doing this- uploading to say, rapidshare is free!

Thanks and all the best!

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